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1.

001-es BibID:BIBFORM019984
Első szerző:Halleskog, Carina
Cím:WNT signaling in activated microglia is proinflammatory / Carina Halleskog, Jan Mulder, Jenny Dahlström, Ken Mackie, Tibor Hortobágyi, Heikki Tanila, Lakshman Kumar Puli, Katrin Färber, Tibor Harkany, Gunnar Schulte
Dátum:2011
ISSN:0894-1491
Megjegyzések:Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased β-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimer's disease. We substantiate disease-associated β-catenin signaling in microglia in vivo by showing age-dependent β-catenin accumulation in mice with Alzheimer's-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize β-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, β-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor α. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of β-catenin-signaling networks in this cell type.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Glia. - 59 : 1 (2011), p. 119-131. -
További szerzők:Mulder, Jan Dahlström, Jenny Mackie, Ken Hortobágyi Tibor (1965-) (patológus) Tanila, Heikki Kumar Puli, Lakshman Färber, Katrin Harkány Tibor Schulte, Gunnar
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2.

001-es BibID:BIBFORM020091
Első szerző:Harkány Tibor
Cím:Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity : relevance to Alzheimer's disease / Tibor Harkany, Tibor Hortobágyi, Maria Sasvári, Csaba Kónya, Botond Penke, Paul G. M. Luiten, Csaba Nyakas
Dátum:1999
ISSN:0278-5846
Megjegyzések:1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition and processing, and memory formation. A beta fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary conservation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isotope-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions. During the past decade, acute injection, prolonged mini-osmotic brain perfusion approaches or A beta infusions into the blood circulation were developed in order to investigate the effects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed primary targets of acute neurotoxicity screening, but functional consequences of A beta infusions were primarily demonstrated following either intracerebroventricular or basal forebrain (medial septum or magnocellular basal nucleus (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta is located within the beta(25-35) sequence, the flanking peptide regions influence not only the folding properties of the A beta fragments, but also their in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neuron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a critical role for N-methyl-D-aspartate (NMDA) receptors was postulated in the neurotoxic processes. Additionally, A beta s might become internalized, either after their selective binding to cell-surface receptors or after membrane association in consequence of their highly lipophilic nature, and induce free radical generation and subsequent oxidative injury. Ca(2+)-mediated neurotoxic events and generation of oxygen free radicals may indeed potentiate each other, or even converge to the same neurotoxic events, leading to cell death. 6. Neuroprotection against A beta toxicity was achieved by both pre- and post-treatment with NMDA receptor channel antagonists. Moreover, direct radical-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity with high efficacy. Interestingly, combined drug treatments did not necessarily result in additive enhanced neuroprotection. 7. Similarly to the blockade of NMDA receptors, the neurotoxic action of A beta s could be markedly decreased by pharmacological manipulation of voltage-dependent Ca(2+)-channels, serotonergic IA or adenosine A1 receptors, and by drugs eliciting membrane hyperpolarization or indirect blockade of Ca(2+)-mediated intracellular consequences of intracerebral A beta infusions. 8. A beta neurotoxicity might be dose-dependently modulated by trace metals. In spite of the fact that zinc (Zn) may act as a potent inhibitor of the NMDA receptor channel, high Zn doses accelerate A beta fibril formation, stabilize the beta-sheet conformation and thereby potentiate A beta neurotoxicity. Combined trace element supplementation with Se, Mn, or Mg, which prevails over the expression of detoxifying enzymes or counteracts intracellular elevations of Ca2+, may reduce the neurotoxic impact of A beta s. 9. Alterations in the regulatory functions of the hypothalamo-pituitary-adrenal axis may contribute significantly to neurodegenerative changes in the brain. Furthermore, AD patients exhibit substantially increased circadia
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Progress In Neuro-Psychopharmacology and Biological Psychiatry. - 23 : 6 (1999), p. 963-1008. -
További szerzők:Hortobágyi Tibor (1965-) (patológus) Sasvári Mária Penke Botond Kónya Csaba Luiten, Paul G. M. Nyakas Csaba
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3.

001-es BibID:BIBFORM020087
Első szerző:Harkány Tibor
Cím:Short-term consequences of N-methyl-D-aspartate excitotoxicity in rat magnocellular nucleus basalis : effects on in vivo labelling of cholinergic neurons / T. Harkany, J. Grosche, J. Mulder, K. M. Horvath, J. Keijser, T. Hortobágyi, P. G. M. Luiten, W. Härtig
Dátum:2001
ISSN:0306-4522
Megjegyzések:Cholinergic neurons of the basal forebrain form one of the neuron populations that are susceptible to excitotoxic injury. Whereas neuropharmacological studies have aimed at rescuing cholinergic neurons from acute excitotoxic attacks, the short-term temporal profile of excitotoxic damage to cholinergic nerve cells remains largely elusive. The effects of N-methyl-D-aspartate (NMDA) infusion on cytochemical markers of cholinergic neurons in rat magnocellular nucleus basalis were therefore determined 4, 24 and 48 h post-lesion. Additionally, the influence of excitotoxic damage on the efficacy of in vivo labelling of cholinergic neurons with carbocyanine 3-192IgG was investigated. Carbocyanine 3-192IgG was unilaterally injected in the lateral ventricle. Twenty-four hours later, NMDA (60 nM/microl) was infused in the right magnocellular nucleus basalis, while control lesions were performed contralaterally. Triple immunofluorescence labelling for carbocyanine 3-192IgG, NMDA receptor 2A and B subunits and choline-acetyltransferase (ChAT) was employed to determine temporal changes in NMDA receptor immunoreactivity on cholinergic neurons. The extent of neuronal degeneration was studied by staining with Fluoro-Jade. Moreover, changes in the numbers of ChAT or p75 low-affinity neurotrophin receptor immunoreactive neurons, and the degree of their co-labelling with carbocyanine 3-192IgG were determined in basal forebrain nuclei. The effects of NMDA-induced lesions on cortical projections of cholinergic nucleus basalis neurons were studied by acetylcholinesterase (AChE) histochemistry. Characteristic signs of cellular damage, as indicated by decreased immunoreactivity for NMDA receptors, ChAT and p75 low-affinity neurotrophin receptors, were already detected at the shortest post-lesion interval investigated. Fluoro-Jade at 4 h post-lesion only labelled the core of the excitotoxic lesion. Longer survival led to enhanced Fluoro-Jade staining, and to the decline of ChAT immunoreactivity reaching a maximum 24 h post-surgery. Significant loss of p75 low-affinity neurotrophin receptor immunoreactivity and of cortical AChE-positive projections only became apparent 48 h post-lesion. Carbocyanine 3-192IgG labelling in the ipsilateral basal forebrain exceeded that of the contralateral hemisphere at all time points investigated and progressively declined in the damaged magnocellular nucleus basalis up to 48 h after NMDA infusion. The present study indicates that excitotoxic lesion-induced alteration of cholinergic neuronal markers is a rapid and gradual process reaching its maximum 24 h post-surgery. Furthermore, in vivo labelling of cholinergic neurons may be applied to indicate neuronal survival under pathological conditions, and enable to follow their degeneration process under a variety of experimental conditions.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neuroscience. - 108 : 4 (2001), p. 611-627. -
További szerzők:Grosche, Jens Mulder, Jan Horváth Katalin M. Keijser, J. Hortobágyi Tibor (1965-) (patológus) Luiten, Paul G. M. Härtig, Wolfgang
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4.

001-es BibID:BIBFORM020073
Első szerző:Harkány Tibor
Cím:Distinct subsets of nucleus basalis neurons exhibit similar sensitivity to excitotoxicity / Tibor Harkany, Csaba Varga, Jens Grosche, Jan Mulder, Paul G. M. Luiten, Tibor Hortobágyi, Botond Penke, Wolfgang Härtig
Dátum:2002
ISSN:0959-4965
Megjegyzések:Excitotoxic lesions in the magnocellular nucleus basalis (MBN) lead to a significant damage of cholinergic neurons concomitant with increased amyloid precursor protein (APP) expression in the cerebral cortex. However, the sensitivity of non-cholinergic neurons to excitotoxicity, and changes of APP expression in the damaged MBN are still elusive. Hence, we performed multiple-labeling immunocytochemistry for choline-acetyltransferase (ChAT), neuron-specific nuclear protein (NeuN) and APP 4, 24, and 48 h after NMDA infusion in the MBN. Whereas all cholinergic neurons were immunoreactive for NeuN, this neuronal marker also labeled a population of ChAT-immunonegative non-cholinergic neurons. Both neuron populations exhibited a similar degree of sensitivity to NMDA excitotoxicity that became evident as early as 4 h post-lesion. Cholinergic MBN neurons showed abundant APP immunoreactivity (approximately 90%), while only a fraction (approximately 20-30%) of non-cholinergic neurons expressed the protein. Remarkably, cholinergic but not non-cholinergic neurons retained their APP immunoreactivity after NMDA infusion. In conclusion, cholinergic MBN neurons are not preferentially sensitive to short-term excitotoxicity, but are one of the major sources of APP in the basal forebrain.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neuroreport. - 13 : 6 (2002), p. 767-772. -
További szerzők:Varga Csaba (orvos) Grosche, Jens Mulder, Jan Luiten, Paul G. M. Hortobágyi Tibor (1965-) (patológus) Penke Botond Härtig, Wolfgang
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5.

001-es BibID:BIBFORM020099
Első szerző:Hortobágyi Tibor (patológus)
Cím:Vein of Galen malformation combined with atrial septal defect in a neonate / T. Hortobágyi, Á. Szűts, M. Csenki, T. Harkany, Z. Zádor, M. Katona, I. Bódi
Dátum:2003
ISSN:0722-5091
Megjegyzések:An arteriovenous fistula (AVF) is an abnormal connection between an artery and a vein, whereby the interconnecting capillary network is missing. Such a malformation frequently occurs in the deep midline regions of the brain, and the subsequent increased flow into the draining vein of Galen substantially dilates in an aneurysmal manner. Congenital forms of the aneurysmal dilatation of the vein of Galen (AVG) often lead to death in the neonatal period, predominantly due to cardiac failure caused by the increased venous inflow as a consequence of the intracerebral arteriovenous shunting. In the presented case a male baby suffered from a rare combination of a cerebral AVF and an atrial septal defect (ASD). He was born at week 38 of pregnancy and subsequently developed tachydyspnoe. Ultrasound (US) and CT scans revealed a large bilateral AVF with dilated basal venous sinuses, hydrocephalus and brain atrophy. In the heart, severe right ventricular hypertrophy, patent ductus arteriosus and an ASD were detectable by US. Neurosurgical consultation rejected the possibility of an operative treatment due to size and localization of the lesion and the existing irreversible brain damage. The child died because of cardiac failure 6 days after birth. Autopsy examination in the brain demonstrated a large conglomerate of dilated blood vessels predominantly in the midline and left occipital lobe, edema and hydrocephalus. In the heart, the ASD detected by US proved to be an ostium secundum-type lesion. Histologically, the conglomerate of vessels revealed features of an AVF and matched the characteristics of AVG. Consequences of chronic ischemic brain injury were also present, with ferruginated neurons suggesting intrauterine damage caused by a congenital AVF. Based on data in the literature, we assume that the left-to-right shunt due to increased venous influx into the heart caused not only cardiomegaly, but may have also interfered with the normal development of the atrial septum leading to an ASD, contributing to the rapid progression of the cardiac failure.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Clinical Neuropathology. - 22 : 4 (2003), p. 193-198. -
További szerzők:Szűts Áron Csenki Marianna (gyermekorvos) Harkány Tibor Zádor Zsolt Katona Márta Bódi István (1967-) (neuropatológus)
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6.

001-es BibID:BIBFORM020093
Első szerző:Hortobágyi Tibor (patológus)
Cím:Neurotrophin-mediated neuroprotection by solid fetal telencephalic graft in middle cerebral artery occlusion : a preventive approach / T. Hortobágyi, T. Harkany, R. Reisch, R. Urbanics, M. Kálmán, C. Nyakas, Z. Nagy
Dátum:1998
ISSN:0361-9230
Megjegyzések:In the present study, embryonic rat neocortex was implanted into the parietal subcortical area of adult naive animals. On the 7th day, the middle cerebral artery was permanently occluded ipsilateral to the graft. Twenty-four hours after middle cerebral artery occlusion, the extent of infarct was visualized by means of 2,3,5-triphenyltetrazolium chloride histochemistry and quantified in four different standardized coronal plains. Subsequently, the effects of fetal tissue grafting and those of transplantation were identified by using glial fibrillary acidic protein and nerve growth factor immunocytochemistry. The grafts integrated well into their new environment and significantly reduced the size of infarct in middle cerebral artery-occluded animals compared with both sham-operated and control rats 24 h postoperation. The underlying mechanism of this phenomenon might be an increased neurotrophic, particularly nerve growth factor, release by the grafted fetal tissue. Moreover, reactive astroglial cells may also trigger the neuroprotection by additional ischemia-induced nerve growth factor release. The present data demonstrate the potential neurotrophin-mediated protective effects of fetal brain tissue implanted into the adult rat brain before unilateral middle cerebral artery occlusion and the beneficial effects of astrocyte activation.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Brain Research Bulletin. - 47 : 2 (1998), p. 185-191. -
További szerzők:Harkány Tibor Reisch, R. Urbanics R. Kálmán M. Nyakas Csaba Nagy Zoltán (1942-) (neurológus)
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7.

001-es BibID:BIBFORM020088
Első szerző:Hortobágyi Tibor (patológus)
Cím:A novel brain trauma model in the mouse : effects of dexamethasone treatment / T. Hortobágyi, S. Hortobágyi, C. Görlach, T. Harkany, Z. Benyó, T. Görögh, W. Nagel, M. Wahl
Dátum:2000
ISSN:0031-6768
Megjegyzések:We describe a novel methodological approach for inducing cold lesion in the mouse as a model of human cortical contusion trauma. To validate its reproducibility and reliability, dexamethasone (Dxm) was repeatedly applied to demonstrate possible antioedematous drug effects. Following the induction of anaesthesia with halothane, the dura was exposed via trephination. Using a micromanipulator a pre-cooled (-78 degrees C) copper cylinder, 3 mm in diameter, was pressed down to a depth of 1 mm onto the dura for 30 s under microscopic control. The body temperature was held constant at 37 degrees C throughout the procedure. Blood pressure (BP), measured by a modified photosensor-monitored tail-cuff method, and acid-base status were not significantly different when analysed before and after cold lesion and prior to sacrifice. However, there was a marginal mixed respiratory and metabolic acidosis. The antioedematous action of Dxm was studied in four standard pre-and post-treatment paradigms: 2x0.5 mg/kg (II), 2x12.5 mg/kg (III) and 4x6.25 mg/kg (IV: 3x pre-, 1x post-treatment: V: 1x pre-, 3x post-treatment). Physiological saline injections served as controls. High doses of Dxm (III-V) significantly attenuated the cold-lesion-induced loss of body mass. Dxm treatment also resulted in a reduction of brain water content (III; P<0.05), and brain swelling (IV; P<0.05) in the lesioned hemisphere, relative to controls. In conclusion, we have characterized a novel cold lesion model in the mouse to mimic traumatic brain injury and the beneficial effect of Dxm treatment on the extent of brain oedema.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Pflügers Archiv. - 441 : 2-3 (2000), p. 409-415. -
További szerzők:Hortobágyi Szabolcs Görlach, Christoph Harkány Tibor Benyó Zoltán Görögh Tibor Nagel, W. Wahl, Michael
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8.

001-es BibID:BIBFORM020071
Első szerző:Hortobágyi Tibor (patológus)
Cím:Inhibition of neuronal nitric oxide synthase-mediated activation of poly(ADP-ribose) polymerase in traumatic brain injury : neuroprotection by 3-aminobenzamide / T. Hortobágyi, C. Görlach, Z. Benyó, Z. Lacza, S. Hortobágyi, M. Wahl, T. Harkany
Dátum:2003
ISSN:0306-4522
Megjegyzések:Focal traumatic injury to the cerebral cortex is associated with early activation of the neuronal isoform of nitric oxide synthase (nNOS), where high concentrations of nitric oxide-derived free radicals elicit extensive DNA damage. Subsequent activation of the nuclear repair enzyme poly(ADP-ribose) polymerase (PARP) causes a severe energy deficit leading to the ultimate demise of affected neurons. Little is known about the temporal relationship of nNOS and PARP activation and the neuroprotective efficacy of their selective blockade in traumatic brain injury. To determine the relationship of nNOS and PARP activation, brain injury was induced by cryogenic lesion to the somatosensory cortex applying a pre-cooled cylinder after trephination for 6 s to the intact dura mater. Pre-treatment with 3-bromo-7-nitroindazole (BrNI; 25 mg/kg, i.p.), and pre- or combined pre- and post-treatment with 3-aminobenzamide (AB; 10 mg/kg (i.c.v.) or 10 mg/kg/h (i.p.)) were used to inhibit nNOS and PARP, respectively. Cold lesion-induced changes in the somatosensory cortex and neuroprotection by BrNI and AB were determined using immunocytochemistry and immunodot-blot for detection of poly(ADP-ribose; PAR), the end-product of PARP activation, and the triphenyltetrazolium-chloride assay to assess lesion volume. PAR immunoreactivity reached its peak 30 min post-lesion and was followed by gradual reduction of PAR immunolabeling. BrNI pre-treatment significantly decreased the lesion-induced PAR concentration in damaged cerebral cortex. Pre-treatment by i.c.v. infusion of AB markedly diminished cortical PAR immunoreactivity and significantly reduced the lesion volume 24 h post-injury. In contrast, i.p. AB treatment remained largely ineffective. In conclusion, our data indicate early activation of PARP after cold lesion that is, at least in part, related to nNOS induction and supports the relevance of nNOS and/or PARP inhibition to therapeutic approaches of traumatic brain injury.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neuroscience. - 121 : 4 (2003), p. 983-990. -
További szerzők:Görlach, Christoph Benyó Zoltán Lacza Zsombor Hortobágyi Szabolcs Wahl, Michael Harkány Tibor
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9.

001-es BibID:BIBFORM020100
Első szerző:Härtig, Wolfgang
Cím:Functional recovery of cholinergic basal forebrain neurons under disease conditions : old problems, new solutions? / Wolfgang Härtig, Andreas Bauer, Kurt Brauer, Jens Grosche, Tibor Hortobágyi, Botond Penke, Reinhard Schliebs, Tibor Harkany
Dátum:2002
Megjegyzések:Recognition of the involvement of cholinergic neurons in the modulation of cognitive functions and their severe dysfunction in neurodegenerative disorders, such as Alzheimer's disease, initiated immense research efforts aimed at unveiling the anatomical organization and cellular characteristics of the basal forebrain (BFB) cholinergic system. Concomitant with our unfolding knowledge about the structural and functional complexity of the BFB cholinergic projection system, multiple pharmacological strategies were introduced to rescue cholinergic nerve cells from noxious attacks; however, a therapeutic breakthrough is still awaited. In this review, we collected recent findings that significantly contributed to our better understanding of cholinergic functions under disease conditions, and to the design of effective means to restore lost or damaged cholinergic functions. To this end, we first provide a brief survey of the neuroanatomical organization of BFB nuclei with emphasis on major evolutionary differences among mammalian species, in particular rodents and primates, and discuss limitations of the translation of experimental data to human therapeutic applications. Subsequently, we summarize the involvement of cholinergic dysfunction in the pathogenesis of severe neurological conditions, including stroke, traumatic brain injury, virus encephalitis and Alzheimer's disease, and emphasize the critical role of pro-inflammatory cytokines as common mediators of cholinergic neuronal damage. Moreover, we review leading functional concepts on the limited recovery of cholinergic neurons and their impaired plastic re-modeling, as well as on the hampered interplay of the ascending cholinergic and monoaminergic projection systems under neurodegenerative conditions. In addition, recent advances in the dynamic labeling of living cholinergic neurons by fluorochromated antibodies, referred to as in vivo labeling, and novel neuroimaging approaches as potential diagnostic tools of progressive cholinergic decline are surveyed. Finally, the potential of cell replacement strategies using embryonic and adult stem cells, and multipotent neural progenitors, as a means to recover damaged cholinergic functions, is discussed.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Reviews in the Neurosciences. - 13 : 2 (2002), p. 95-165. -
További szerzők:Bauer, Andreas Brauer, Kurt Grosche, Jens Hortobágyi Tibor (1965-) (patológus) Penke Botond Schliebs, Reinhard Harkány Tibor
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10.

001-es BibID:BIBFORM019971
Első szerző:Mulder, Jan
Cím:Molecular reorganization of endocannabinoid signalling in Alzheimer's disease / Jan Mulder, Misha Zilberter, Susana J. Pasquaré, Alán Alpár, Gunnar Schulte, Samira G. Ferreira, Attila Köfalvi, Ana M. Martín-Moreno, Erik Keimpema, Heikki Tanila, Masahiko Watanabe, Ken Mackie, Tibor Hortobágyi, Maria L. de Ceballos, Tibor Harkany
Dátum:2011
ISSN:0006-8950
Megjegyzések:Retrograde messengers adjust the precise timing of neurotransmitter release from the presynapse, thus modulating synaptic efficacy and neuronal activity. 2-Arachidonoyl glycerol, an endocannabinoid, is one such messenger produced in the postsynapse that inhibits neurotransmitter release upon activating presynaptic CB(1) cannabinoid receptors. Cognitive decline in Alzheimer's disease is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-arachidonoyl glycerol signalling impairs synaptic neurotransmission in Alzheimer's disease. Comparative protein profiling and quantitative morphometry showed that overall CB(1) cannabinoid receptor protein levels in the hippocampi of patients with Alzheimer's disease remain unchanged relative to age-matched controls, and CB(1) cannabinoid receptor-positive presynapses engulf amyloid-β-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase α and β isoforms, synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimer's (Braak stage VI), with ectopic sn-1-diacylglycerol lipase β expression found in microglia accumulating near senile plaques and apposing CB(1) cannabinoid receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine hydrolase α/β-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable Alzheimer's disease (Braak stage III). However, Alzheimer's pathology differentially impacts serine hydrolase α/β-hydrolase domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase α/β-hydrolase domain-containing 6 expression ceases in neurofibrillary tangle-bearing pyramidal cells. In contrast, pyramidal cells containing hyperphosphorylated tau retain monoacylglycerol lipase expression, although at levels significantly lower than in neurons lacking neurofibrillary pathology. Here, monoacylglycerol lipase accumulates in CB(1) cannabinoid receptor-positive presynapses. Subcellular fractionation revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimer's tissues, suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimer's disease by demonstrating significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with amyloid-β. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing 2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling, particularly around senile plaques, can exacerbate synaptic failure in Alzheimer's disease.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Brain. - 134 : 4 (2011), p. 1041-1060. -
További szerzők:Zilberter, Misha Pasquaré, Susana J. Alpár Alán Schulte, Gunnar Ferreira, Samira G. Köfalvi Attila Martín-Moreno, Ana M. Keimpema, Erik Tanila, Heikki Watanabe, Masahiko Mackie, Ken Hortobágyi Tibor (1965-) (patológus) de Ceballos, Maria L. Harkány Tibor
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11.

001-es BibID:BIBFORM020299
Első szerző:Zádor Zsolt
Cím:Apoptózis fokális agyi ischaemiában / Zádor Zsolt, Lacza Zsombor, Benyó Zoltán, Harkány Tibor, Hortobágyi Tibor
Dátum:2003
Megjegyzések:Az ischaemiás stroke, amely hazánkban is vezető halálok, gócos agyi vérellátási zavar következtében alakul ki. Az ischaemiás sejtpusztulás döntően hevenyen lezajló nekrózis formájában jelentkezik. Terápiás szempontból is jelentős sajátosság, hogy a nekrotikus agyterület határzónájában késleltetett sejtvesztés zajlik, amely az apoptózis jellegzetességeit mutatja. Az apoptózis korunk orvosbiológiai kutatásainak egyik legintenzívebben vizsgált folyamata, mechanizmusának jobb megismerése számos betegség, köztük az ischaemiás stroke eredményesebb terápiáját ígéri. A szerzők összefoglalják a fokális agyi ischaemia neurológiai jellegzetességeit, az apoptotikus és a nekrotikus sejtpusztulás morfológiai jellemzőit. Az apoptózis mechanizmusát a gének szintjén zajló döntési és sejtszintű végrehajtási fázisra osztva tekintik át. Tárgyalják a fiziológiásan egyensúlyban lévő pro- és antiapoptotikus gének és fehérjetermékeik döntési fázisban bekövetkező arányeltolódását, az apoptotikus kaszkád beindításában kulcsszerepet játszó kalciumhomeosztázis- felbomlás, energiadepletio és mitochondrialis diszfunkció sajátosságait. Bemutatják az apoptózisban fontos szerepet játszó kaszpázokat és a végrehajtási fázis három lehetséges eseménysorát: az intrinszik és az extrinszik kaszpáz utat, valamint a kaszpázfüggetlen intracelluláris jelátviteli rendszert. Ismertetik a végrehajtási fázisban jelentkező idegsejtmembrán-károsodás molekuláris mechanizmusát, a fehérjeszintézis sajátos megváltozásának, az üzenetkiválasztásnak a jellemzőit. Hangsúlyozzák a késői reperfúzió apoptózis-végrehajtásban játszott jelentős szerepét. Bemutatják az apoptózis eseménysorának lehetséges terápiás célpontjait, ismertetik az állatkísérletekben eredményesnek bizonyult antiapoptotikus beavatkozásokat és azok humán alkalmazásának kilátásait.
Tárgyszavak:Orvostudományok Elméleti orvostudományok magyar nyelvű folyóiratközlemény hazai lapban
Megjelenés:Ideggyógyászati Szemle. - 56 : 7/8 (2003), p. 216-228. -
További szerzők:Lacza Zsombor Benyó Zoltán Harkány Tibor Hortobágyi Tibor (1965-) (patológus)
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12.

001-es BibID:BIBFORM020296
Első szerző:Zádor Zsolt
Cím:Neuroprotekció agyi ischaemiában : kételyek és remények / Zádor Zsolt, Benyó Zoltán, Lacza Zsombor, id. Hortobágyi Tibor, Harkány Tibor, Hortobágyi Tibor
Dátum:2004
Megjegyzések:Az ischaemiás stroke-ban a vérátáramlás javítása és az eseménysor közvetlen neuroprotektív befolyásolása a két fő lehetséges terápiás stratégia - ezt számos állatkísérlet alátámasztja. Az eddigi klinikai gyógyszerkipróbálásokban az ischaemia neurotoxikus eseménysorának direkt blokkolása eredménytelen maradt, noha számos vegyület klinikai kipróbálása még nem zárult le. Újabb terápiás megközelítésekre van szükség. Ismertetjük a kísérletes eredményeket és a kapcsolódó klinikai gyógyszerkipróbálások következtetéseit. A humán vizsgálatok sikertelenségének főbb okai: 1. az egyes szerek állatkísérletekben vizsgált neuroprotektív hatását gyakran a szubletálisan károsodott agyterület (penumbra) "visszatérése", az infarktus kiterjedésének csökkenése igazolta, de a neurológiai funkció értékelése elmaradt; 2. a beteg életminőségét döntően meghatározó intellektus és magasabb kérgi funkciók vizsgálata állatkísérletekben nem, vagy csak igen áttételesen lehetséges; 3. a klinikai kipróbálásban gyakran heterogén és kis létszámú a betegpopuláció, nem optimális a vizsgálati protokoll, valamint a szubakut és a krónikus fázis elemzése és farmakoterápiája háttérbe szorul. Az ischaemiás stroke állatmodelljeit összevetve a humán kórfolyamattal megállapítható, hogy a kísérletes eredmények emberi megbetegedésre vonatkoztatása buktatókat rejt. Az agyszövet sejtjei közötti szoros funkcionális és morfológiai kapcsolat, a neurotoxikus kaszkád és a reparáció folyamatának hónapokig elhúzódó volta, valamint az eddigi klinikai vizsgálatok tapasztalatai azt sugallják, hogy hosszabb időintervallumban és több támadásponton ható gyógyszer-kombinációk (terápiás koktélok) alkalmazása, valamint az agyi plaszticitást serkentő beavatkozások adhatnak kedvezőbb eredményt.
Tárgyszavak:Orvostudományok Klinikai orvostudományok magyar nyelvű folyóiratközlemény hazai lapban
Megjelenés:Ideggyógyászati Szemle. - 57 : 3-4 (2004), p. 81-93. -
További szerzők:Benyó Zoltán Lacza Zsombor Hortobágyi Tibor (id.) Harkány Tibor Hortobágyi Tibor (1965-) (patológus)
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